Project Background/Rationale. About 15% of service members have sustained a traumatic brain injury (TBI) on one or more occasions while deployed in Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND). The long-term effects of TBI in civilians and in Vietnam veterans are known to include neurodegenerative conditions. However, little is currently known about TBI sustained during the ongoing conflicts and it is timely to investigate the chronic effects of blast and non-blast-related TBI in OEF/OIF/OND veterans and service members. Project Objectives. The study's broad objective is to characterize the chronic effects of TBI sustained by OEF/OIF/OND veterans and service members, and the specific aims include the evaluation of these effects on cognition, neurologic status, and functional outcome in relation to secondary pathology shown by multimodality brain imaging. Related objectives include an examination of how genetics, cognitive reserve, and brain reserve moderate the chronic effects of TBI on outcome. Project Methods. This dual cohort, longitudinal study would enroll 200 OEF/OIF/OND veterans and service members, including 150 who reported at least one TBI and 50 with an injury to body regions other than the brain or no injury. Participants would be enrolled at the Michael E. De Bakey Veterans Affairs Medical Center (MEDVAMC) and from a coordinated site at Brooke Army Medical Center (BAMC) and Darnall Army Medical Center (DAMC) at Fort Hood. Following informed consent and screening for eligibility, participants who are least two months post-injury would complete a baseline, in-person assessment at the MEDVAMC or BAMC/DAMC that would include cognitive testing, functional status, neurologic examination, and brain imaging. Magnetic resonance imaging (MRI) would be performed to assess brain region and total white matter volumes and cortical thickness, diffusion tensor imaging (DTI) would examine microstructural integrity of white matter tracts, resting state functional connectivity MRI (fcMRI) would measure spontaneous brain activation, and magnetic resonance spectroscopy (MRS) would assess levels of neurotransmitters that are thought to be altered following TBI. A blood draw would provide serum for genotyping. Follow-ups would include web-based assessment of cognition and functional status at six and 18 months after baseline and a second in-person assessment at 12 months that would repeat the outcomes measurement and brain imaging that had been performed at baseline. Data would be archived in an object-oriented database designed for the storage and mining of scientific data in collaborative environments. Data management and statistical analysis would be performed by the senior project statistician at the MEDVAMC in coordination with the other study investigators. Administrative oversight would be provided by subgroups of investigators and project staff organized by their expertise and roles, including Administration, Recruitment and Retention, Imaging, Neuropsychological Assessment, Neurological Examination, Genetics, and Data Management/Analysis. To ensure uniform procedures between the project sites, a workshop would be held and a project manual completed during the first three months. Quality assurance (QA) testing of the similar MRI scanners at the two project sites would ensure high quality image data and audits of the cognitive and behavioral data, including monitoring by neuropsychologists, would provide QA for those measures. Relevance to the VA Health Mission. The chronic effects of single and repetitive TBI sustained by OEF/OIF/OND veterans and service members are poorly understood, but potentially include neurodegenerative conditions that impact the long-term health and quality of life of veterans and their families. This project would enhance the capability of VHA to monitor and identify late effects of TBI, including the use of advanced brain imaging to inform planning of rehabilitation and healthcare resources. PUBLIC HEALTH RELEVANCE: Longitudinal studies of combat-related TBI are sparse, and the neural mechanisms mediating long-term pathology and outcome are poorly understood. Establishing the long-term effects of combat-related TBI would provide critical information to veterans who are concerned about their own risk for developing neurodegenerative conditions later in life and would inform public policy to ensure that appropriate resources are available for the future care of veterans. There is also a knowledge gap regarding the effects of PTSD and depressive symptoms on brain function and outcome following combat-related TBI. In addition, this investigation will elucidate the potential role of host factors such as genetics and cognitive and brain reserve. This represents a unique opportunity to leverage the resources of ongoing cross-sectional studies, expand their scope, and extend them into a longitudinal design. We anticipate that this will allow a better understanding of TBI and provide the basis for development of new screening tools and rehabilitation procedures.